Investigating the molecular etiology of disorders caused by disturbed mineral metabolism has been instrumental in identifying new circulating regulators of phosphate homeostasis, collectively referred to as 'phosphatonins.' We identified the phosphatonin Fibroblast growth factor-23 (FGF23) in a positional cloning approach to isolate the gene for autosomal dominant hypophosphatemic rickets (ADHR), characterized by renal phosphate wasting, rickets/osteomalacia, and fracture. A unique and clinically important aspect of ADHR that distinguishes this syndrome from other disorders associated with elevated FGF23 is that ADHR patients can have symptomatic cycling by rapidly progressing from normophosphatemia in carrier status, to full disease onset. Further, it is not known why hypophosphatemic ADHR patients are unable to down-regulate FGF23 during active disease, as low serum phosphate is typically a strong suppressor of this gene in vivo. This paradox highlights the hypothesis that a biological stimulus outside of the known 'normal' endocrine feedback loops can drive FGF23 production. Therefore, the molecular mechanisms by which FGF23 directs phosphate handling are incompletely understood. In accord with our current aims, we have identified novel mechanisms controlling Fgf23 expression and regulation that may underlie late-onset ADHR. The delayed disease course in ADHR patients can be associated with physiological states prone to low iron status, such as puberty and following pregnancy. Using a novel ADHR R176Q-Fgf23 knock-in mouse, our results show that low serum iron markedly increases bone Fgf23 mRNA. Additionally, we propose that this mRNA increase occurs through a key iron/hypoxic sensing response, which would significantly modify the current paradigms explaining phosphate homeostasis. Our results also support that WT mice can compensate for low-iron induced Fgf23 mRNA by proteolytically cleaving the excess hormone in a secondary regulatory step to maintain normal serum intact Fgf23 and phosphate metabolism. In contrast, the ADHR mice may not fully compensate for elevated Fgf23 mRNA due to the protease resistance of R176Q-Fgf23, leading to increased serum intact hormone and to hypophosphatemic bone disease. In light of our initial findings, important aspects of Fgf23 biology, including the molecular mechanisms dictating increased Fgf23 during onset and progression of ADHR, as well as the regulation of circulating intact Fgf23, and bioactivity through its receptor systems, remain to be defined. Thus, the central hypothesis to be tested is: reduced iron status stimulates a cellular iron/hypoxic sensing response that, in the context of an ADHR mutation, leads to inappropriate, elevated expression of Fgf23 and to over-activity of the Fgf23 receptor signaling complex, resulting in hypophosphatemic bone disease. We expect these studies to provide novel, translational insight into rare and common syndromes of altered FGF23 expression and into the basic biology of phosphate homeostasis.